Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging

Elisabetta Flex, Simone Martinelli, Anke Van Dijck, Andrea Ciolfi, Serena Cecchetti, Elisa Coluzzi, Luca Pannone, Cristina Andreoli, Francesca Clementina Radio, Simone Pizzi, Giovanna Carpentieri, Alessandro Bruselles, Giuseppina Catanzaro, Lucia Pedace, Evelina Miele, Elena Carcarino, Xiaoyan Ge, Chieko Chijiwa, M. E.Suzanne Lewis, Marije Meuwissen & 40 others Sandra Kenis, Nathalie Van der Aa, Austin Larson, Kathleen Brown, Melissa P. Wasserstein, Brian G. Skotko, Amber Begtrup, Richard Person, Maria Karayiorgou, J. Louw Roos, Koen L. Van Gassen, Marije Koopmans, Emilia K. Bijlsma, Gijs W.E. Santen, Daniela Q.C.M. Barge-Schaapveld, Claudia A.L. Ruivenkamp, Mariette J.V. Hoffer, Seema R. Lalani, Haley Streff, William J. Craigen, Brett H. Graham, Annette P.M. van den Elzen, Daan J. Kamphuis, Katrin Õunap, Karit Reinson, Sander Pajusalu, Monica H. Wojcik, Clara Viberti, Cornelia Di Gaetano, Enrico Bertini, Simona Petrucci, Alessandro De Luca, Rossella Rota, Elisabetta Ferretti, Giuseppe Matullo, Bruno Dallapiccola, Antonella Sgura, Magdalena Walkiewicz, R. Frank Kooy, Marco Tartaglia

Research output: Contribution to journalArticle

Abstract

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

Original languageEnglish
Pages (from-to)493-508
Number of pages16
JournalAmerican Journal of Human Genetics
Volume105
Issue number3
DOIs
Publication statusPublished - Sep 5 2019

Fingerprint

Premature Aging
Cell Aging
Histones
Chromatin
DNA Packaging
Frameshift Mutation
Mutation
Chromatin Assembly and Disassembly
Germ-Line Mutation
Mutant Proteins
DNA Replication
S Phase
Intellectual Disability
DNA Repair
Cell Division
Mental Competency
Methylation
Genome
Phenotype
DNA

Keywords

  • accelerated aging
  • cellular senescence
  • chromatin compaction
  • chromatin dynamics
  • chromatin remodeling
  • HIST1H1E
  • linker histone
  • linker histone H1.4
  • methylation profiling
  • replicative senescence

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging. / Flex, Elisabetta; Martinelli, Simone; Van Dijck, Anke; Ciolfi, Andrea; Cecchetti, Serena; Coluzzi, Elisa; Pannone, Luca; Andreoli, Cristina; Radio, Francesca Clementina; Pizzi, Simone; Carpentieri, Giovanna; Bruselles, Alessandro; Catanzaro, Giuseppina; Pedace, Lucia; Miele, Evelina; Carcarino, Elena; Ge, Xiaoyan; Chijiwa, Chieko; Lewis, M. E.Suzanne; Meuwissen, Marije; Kenis, Sandra; Van der Aa, Nathalie; Larson, Austin; Brown, Kathleen; Wasserstein, Melissa P.; Skotko, Brian G.; Begtrup, Amber; Person, Richard; Karayiorgou, Maria; Roos, J. Louw; Van Gassen, Koen L.; Koopmans, Marije; Bijlsma, Emilia K.; Santen, Gijs W.E.; Barge-Schaapveld, Daniela Q.C.M.; Ruivenkamp, Claudia A.L.; Hoffer, Mariette J.V.; Lalani, Seema R.; Streff, Haley; Craigen, William J.; Graham, Brett H.; van den Elzen, Annette P.M.; Kamphuis, Daan J.; Õunap, Katrin; Reinson, Karit; Pajusalu, Sander; Wojcik, Monica H.; Viberti, Clara; Di Gaetano, Cornelia; Bertini, Enrico; Petrucci, Simona; De Luca, Alessandro; Rota, Rossella; Ferretti, Elisabetta; Matullo, Giuseppe; Dallapiccola, Bruno; Sgura, Antonella; Walkiewicz, Magdalena; Kooy, R. Frank; Tartaglia, Marco.

In: American Journal of Human Genetics, Vol. 105, No. 3, 05.09.2019, p. 493-508.

Research output: Contribution to journalArticle

Flex, E, Martinelli, S, Van Dijck, A, Ciolfi, A, Cecchetti, S, Coluzzi, E, Pannone, L, Andreoli, C, Radio, FC, Pizzi, S, Carpentieri, G, Bruselles, A, Catanzaro, G, Pedace, L, Miele, E, Carcarino, E, Ge, X, Chijiwa, C, Lewis, MES, Meuwissen, M, Kenis, S, Van der Aa, N, Larson, A, Brown, K, Wasserstein, MP, Skotko, BG, Begtrup, A, Person, R, Karayiorgou, M, Roos, JL, Van Gassen, KL, Koopmans, M, Bijlsma, EK, Santen, GWE, Barge-Schaapveld, DQCM, Ruivenkamp, CAL, Hoffer, MJV, Lalani, SR, Streff, H, Craigen, WJ, Graham, BH, van den Elzen, APM, Kamphuis, DJ, Õunap, K, Reinson, K, Pajusalu, S, Wojcik, MH, Viberti, C, Di Gaetano, C, Bertini, E, Petrucci, S, De Luca, A, Rota, R, Ferretti, E, Matullo, G, Dallapiccola, B, Sgura, A, Walkiewicz, M, Kooy, RF & Tartaglia, M 2019, 'Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging', American Journal of Human Genetics, vol. 105, no. 3, pp. 493-508. https://doi.org/10.1016/j.ajhg.2019.07.007
Flex, Elisabetta ; Martinelli, Simone ; Van Dijck, Anke ; Ciolfi, Andrea ; Cecchetti, Serena ; Coluzzi, Elisa ; Pannone, Luca ; Andreoli, Cristina ; Radio, Francesca Clementina ; Pizzi, Simone ; Carpentieri, Giovanna ; Bruselles, Alessandro ; Catanzaro, Giuseppina ; Pedace, Lucia ; Miele, Evelina ; Carcarino, Elena ; Ge, Xiaoyan ; Chijiwa, Chieko ; Lewis, M. E.Suzanne ; Meuwissen, Marije ; Kenis, Sandra ; Van der Aa, Nathalie ; Larson, Austin ; Brown, Kathleen ; Wasserstein, Melissa P. ; Skotko, Brian G. ; Begtrup, Amber ; Person, Richard ; Karayiorgou, Maria ; Roos, J. Louw ; Van Gassen, Koen L. ; Koopmans, Marije ; Bijlsma, Emilia K. ; Santen, Gijs W.E. ; Barge-Schaapveld, Daniela Q.C.M. ; Ruivenkamp, Claudia A.L. ; Hoffer, Mariette J.V. ; Lalani, Seema R. ; Streff, Haley ; Craigen, William J. ; Graham, Brett H. ; van den Elzen, Annette P.M. ; Kamphuis, Daan J. ; Õunap, Katrin ; Reinson, Karit ; Pajusalu, Sander ; Wojcik, Monica H. ; Viberti, Clara ; Di Gaetano, Cornelia ; Bertini, Enrico ; Petrucci, Simona ; De Luca, Alessandro ; Rota, Rossella ; Ferretti, Elisabetta ; Matullo, Giuseppe ; Dallapiccola, Bruno ; Sgura, Antonella ; Walkiewicz, Magdalena ; Kooy, R. Frank ; Tartaglia, Marco. / Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging. In: American Journal of Human Genetics. 2019 ; Vol. 105, No. 3. pp. 493-508.
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AU - Flex, Elisabetta

AU - Martinelli, Simone

AU - Van Dijck, Anke

AU - Ciolfi, Andrea

AU - Cecchetti, Serena

AU - Coluzzi, Elisa

AU - Pannone, Luca

AU - Andreoli, Cristina

AU - Radio, Francesca Clementina

AU - Pizzi, Simone

AU - Carpentieri, Giovanna

AU - Bruselles, Alessandro

AU - Catanzaro, Giuseppina

AU - Pedace, Lucia

AU - Miele, Evelina

AU - Carcarino, Elena

AU - Ge, Xiaoyan

AU - Chijiwa, Chieko

AU - Lewis, M. E.Suzanne

AU - Meuwissen, Marije

AU - Kenis, Sandra

AU - Van der Aa, Nathalie

AU - Larson, Austin

AU - Brown, Kathleen

AU - Wasserstein, Melissa P.

AU - Skotko, Brian G.

AU - Begtrup, Amber

AU - Person, Richard

AU - Karayiorgou, Maria

AU - Roos, J. Louw

AU - Van Gassen, Koen L.

AU - Koopmans, Marije

AU - Bijlsma, Emilia K.

AU - Santen, Gijs W.E.

AU - Barge-Schaapveld, Daniela Q.C.M.

AU - Ruivenkamp, Claudia A.L.

AU - Hoffer, Mariette J.V.

AU - Lalani, Seema R.

AU - Streff, Haley

AU - Craigen, William J.

AU - Graham, Brett H.

AU - van den Elzen, Annette P.M.

AU - Kamphuis, Daan J.

AU - Õunap, Katrin

AU - Reinson, Karit

AU - Pajusalu, Sander

AU - Wojcik, Monica H.

AU - Viberti, Clara

AU - Di Gaetano, Cornelia

AU - Bertini, Enrico

AU - Petrucci, Simona

AU - De Luca, Alessandro

AU - Rota, Rossella

AU - Ferretti, Elisabetta

AU - Matullo, Giuseppe

AU - Dallapiccola, Bruno

AU - Sgura, Antonella

AU - Walkiewicz, Magdalena

AU - Kooy, R. Frank

AU - Tartaglia, Marco

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KW - cellular senescence

KW - chromatin compaction

KW - chromatin dynamics

KW - chromatin remodeling

KW - HIST1H1E

KW - linker histone

KW - linker histone H1.4

KW - methylation profiling

KW - replicative senescence

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